Long-chain n-3 polyunsaturated fatty acids (Omega-3) and anti-diabetic drugs thiazolidinediones (TZDs) exhibit additive effects in counteraction of dietary obesity and associated metabolic dysfunctions in mice. The underlying mechanisms need to be clarified. Here, we aimed to learn whether the futile cycle based on the hydrolysis of triacylglycerol and re-esterification of fatty acids (TAG/FA cycling) in white adipose tissue (WAT) could be involved. We compared Omega-3 (30 mg/g diet) and two different TZDs-pioglitazone (50 mg/g diet) and a second-generation TZD, MSDC-0602K (330 mg/g diet)-regarding their effects in C57BL/6N mice fed an obesogenic high-fat (HF) diet for 8 weeks. The diet was supplemented or not by the tested compound alone or with the two TZDs combined individually with Omega-3. Activity of TAG/FA cycle in WAT was suppressed by the obesogenic HF diet. Additive effects in partial rescue of TAG/FA cycling in WAT were observed with both combined interventions, with a stronger effect of Omega-3 and MSDC-0602K. Our results (i) supported the role of TAG/FA cycling in WAT in the beneficial additive effects of Omega-3 and TZDs on metabolism of diet-induced obese mice, and (ii) showed differential modulation of WAT gene expression and metabolism by the two TZDs, depending also on Omega-3.

Cirius Therapeutics Kalamazoo MI 490 07 USA

Laboratory of Adipose Tissue Biology Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 20 Prague 4 Czech Republic

Laboratory of Metabolism of Bioactive Lipids Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 20 Prague 4 Czech Republic

Laboratory of Metabolomics Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 20 Prague 4 Czech Republic

Laboratory of Translational Metabolism Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 20 Prague 4 Czech Republic

NMR Spectroscopy Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemmingovo Namesti 542 2 160 00 Prague 6 Czech Republic

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Omega-3 PUFAs prevent bone impairment and bone marrow adiposity in mouse model of obesity

Novel thiazolidinedione analog reduces a negative impact on bone and mesenchymal stem cell properties in obese mice compared to classical thiazolidinediones

Loss of UCP1 function augments recruitment of futile lipid cycling for thermogenesis in murine brown fat

Adipose tissue-specific ablation of PGC-1β impairs thermogenesis in brown fat